Evolution of Immune Loci Critical in Antigen Recognition

这个项目的重点是适应性免疫系统的进化，它使动物能够对许多不同类型的病原体做出强大和特异的反应。获得性免疫的一个关键特征是由两种抗原受体识别抗原：抗体(由B细胞产生的免疫球蛋白，体液免疫的来源)和T细胞受体(TCR，参与细胞免疫)。由于其特殊的多样性，这些受体可以与广泛的生物分子结合；受体的多样性是由适应性免疫反应特有的独特遗传机制(体细胞基因重排和超突变)创造的。先前的研究表明，地球上最古老的有颌骨的脊椎动物--软骨鱼(包括鲨鱼)--拥有这个系统的所有基本分子硬件。然而，哺乳动物适应性免疫系统的一些元素--淋巴结、骨髓和特殊的淋巴组织，如生发中心--在鲨鱼中是不存在的；因此，鲨鱼提供了一个相对简单的模型来了解适应性免疫的最基本特征。尽管T细胞和B细胞的功能一直被认为是截然不同的，但该实验室在鲨鱼细胞中发现了一种抗原受体NAR-TCR，它在细胞(TCR)和体液(抗体)免疫中使用相同的结构域；它现在还记录了多个鲨鱼T细胞的实例，其特性(例如，免疫球蛋白可变区和体细胞超突变)以前仅归因于B细胞。在这些发现的基础上，该项目将通过探索每种细胞类型可用的免疫遗传机制的边界，重新审视脊椎动物B细胞和T细胞的基本定义。这些边界出人意料的可塑性为脊椎动物免疫系统的进化提供了具有挑衅性的新视角；它也暗示了在包括人类在内的其他脊椎动物中进行免疫反应操纵的新可能性。从高中到研究生阶段的学生研究培训是该项目不可或缺的一部分。

This project focuses on the evolution of the adaptive immune system, which enables animals to respond powerfully and specifically to pathogens of many different types. A key feature of adaptive immunity is antigen recognition by two types of antigen receptors: antibodies (immunoglobulins, produced by B cells, and the source of humoral immunity), and T-cell receptors (TCR; involved in cellular immunity). Because of their extraordinary diversity, these receptors can bind to a wide range of biological molecules; receptor diversity is created by unique genetic mechanisms (somatic gene rearrangement and hypermutation) characteristic of the adaptive immune response. Previous work has shown that the oldest jawed vertebrates on earth, the cartilaginous fish (including sharks), have all of the basic molecular hardware of this system. However, some elements of the mammalian adaptive immune system - lymph nodes, bone marrow, and specialized lymphoid tissue such as germinal centers - are absent in sharks; sharks thus provide a relatively simple model to understand the most fundamental characteristics of adaptive immunity. Although T cells and B cells have been considered quite distinct in function, this laboratory discovered in shark cells an antigen receptor, NAR-TCR, that uses the same domain in both cellular (TCR) and humoral (antibody) immunity; it has also now documented multiple instances of shark T-cells with properties (e.g., immunoglobulin variable domains and somatic hypermutation) previously ascribed only to B-cells. Building on these findings, this project will reexamine the basic definition of vertebrate B and T cells by exploring the boundaries of the immunogenetic mechanisms available to each cell type. The unexpected plasticity of these boundaries offers provocative new perspectives on the evolution of the vertebrate immune system; it also suggests new possibilities for immune response manipulation in other vertebrates, including humans. Student research training from high school through graduate levels is integral to the project.